Vol. 15 Issue 2
On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver
The goal of treatment for chronic hepatitis C viral (HCV) infection is to cure the infection rather than suppress the virus. Historically, a sustained virological response (SVR) defined as undetectable HCV RNA at 24 weeks following the completion of treatment was considered the gold standard to define successful eradication of the virus as a primary endpoint in clinical trials. SVR measured at 12 weeks post-treatment has been shown to be highly concordant with SVR24 in trials of pegylated interferon and ribavirin. The appropriateness and durability of SVR12 as the efficacy endpoint with new oral direct-acting antivirals is less established. A literatura search was performed using PubMed, EMBASE and CENTRAL databases to identify any studies that examined the concordance between SVR24 and earlier time points. Two studies and 4 abstracts were found that performed concordance analyses using positive and negative predictive values. Overall, SVR4 and SVR12 were highly concordant with SVR24 with high positive (> 97%) and negative (> 94%) predictive values; however there was a higher risk of HCV relapse occurring after post-treatment week 4. The majority of the data focused on SVR12 and demonstrated that SVR12 reliably predicted SVR24 in several populations infected with HCV (treatment-naïve, prior null responders, different genotypes) using various new oral direct-acting antiviral regimens. In conclusion, the available data suggests that SVR12 is a reliable assessment of HCV eradication and could be used instead of SVR24 for drug development clinical trials assessing efficacy of new direct-acting antivirals. Data on the long-term durability of SVR12 is still needed.
Oxidative stress is importantly involved in the pathophysiology of various liver diseases. The redox state participates on the course of the inflammatory, metabolic and proliferative liver diseases. The main sources of the reactive oxygen species (ROS) are represented by the mitochondria and cytochrome P450 enzymes in the hepatocyte, Kupffer cells and neutrophils. Cells are provided with efficient molecular strategies to strictly control the intracellular ROS level and to maintain the balance between oxidant and antioxidant molecules. Hepatocytes proteins, lipids and DNA are among the cellular structures to be affected primarily by ROS and reactive nitrogen species (RNS). This process disrupts at cellular and molecular level the structure-function relationship on liver cells at different sites. Therefore, further studies on the molecular mechanisms of the oxidative stress pathways on liver diseases are urgently required, because they could explain the pathogenesis of various liver disorders. Moreover, new methods to evaluate oxidative stress like the oxidative markers among hepatocytes offers the potential to diagnose the degree of liver injury and ultimately to assess the response to pharmacological therapies. In this review, we discuss the molecular, metabolic and aging aspects of the oxidative stress, and the methods to evaluate oxidative stress on liver damage.
Background and aims. CD4+ T cells play an important role in response to hepatitis B virus (HBV) infection. We investigated the change in CD4+ T-cell subpopulations and viral load in patients with chronic HBV infection who were treated with entecavir. Material and methods. Thirty patients with chronic HBV infection were enrolled according to the criteria recommended by the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology. The expressions of signature transcription factors and cytokines of CD4+ T-cell subpopulations were measured in chronic hepatitis B (CHB) patients treated with entecavir treatment. Results. Entecavir treatment significantly attenuated hepatitis B virus DNA load and affected the CD4+ T-cell subsets in CHB patients. A dramatic decrease in the Th17 and Treg cell frequencies and expressions of their related cytokines were found in CHB patients with entecavir treatment. In contrast, entecavir treatment caused a remarkable increase in the Th2 cell frequencies and expressions of their related cytokines. Conclusion. Our results suggested that Th17 and Treg cells were the more sensitive subtypes to entecavir- induced inhibition of HBV replication compared to Th1 and Th2 cells in chronic HBV patients.
Background and objective. Steatohepatitis is a common cause of liver disease due to alcohol (ALD) or non-alcoholic fatty liver disease (NAFLD). We performed this study to compare natural history of ALD and NAFLD. Material and methods. Retrospective analysis of ALD or NAFLD patients managed at our center (2007-2011). ALD diagnosed by excluding other liver diseases (except HCV) and alcohol abuse of > 40 g/d in women and > 60 g/d in men for > 5 years. NAFLD diagnosed by excluding other liver diseases and a history of alcohol use of < 10 g/d. Cirrhosis was diagnosed using biopsy for uncertain clinical diagnosis. Results. Compared to patients with NAFLD (n = 365; mean age 50 yrs; 43% males; 53% diabetic), ALD patients (n = 206; mean age 51 yrs; 68% males; 24% diabetic) presented more often with cirrhosis or complications(46vs. 12%; P< 0.0001) with a higher MELD score (13 ± 7 vs. 8 ± 8; P<0.0001). On logistic regression, ALD diagnosis was associated with presence of cirrhosis by over 4-fold (4.1 [1.8-9.1]) even after excluding 23 patients with concomitant HCV. Over median follow up of about 3 and 4 yrs among ALD and NAFLD patients respectively, ALD patients more frequently developed cirrhosis or its complications including HCC with worse transplant free survival (90 vs. 95%; P = 0.038). Conclusions. Compared to NAFLD, ALD patients present at an advanced stage of liver disease with a faster progression on follow-up. Prospective multicenter studies are needed to identify potential barriers to early referral of ALD patients as basis for development of strategies to improve outcome of patients with ALD.
Background. This study aims to identify key genes and pathways involved in non-alcoholic fatty liver disease (NAFLD). Material and methods. The dataset GSE48452 was downloaded from Gene Expression Omnibus, including 14 control liver samples, 27 healthy obese samples, 14 steatosis samples and 18 nonalcoholic steatohepatitis (NASH) samples. Differentially expressed genes (DEGs) between controls and other samples were screened through LIMMA package. Then pathway enrichment analysis for DEGs was performed by using DAVID, and alterations of enriched pathways were determined. Furthermore, protein-protein interaction (PPI) networks were constructed based on the PPI information from HPRD database, and then, networks were visualized through Cytoscape. Additionally, interactions between microRNAs (miRNAs) and pathways were analyzed via Fishers exact test. Results. A total of 505, 814 and 783 DEGs were identified for healthy obese, steatosis and NASH samples in comparison with controls, respectively. DEGs were enriched in ribosome (RPL36A, RPL14, etc.), ubiquitin mediated proteolysis (UBE2A, UBA7, etc.), focal adhesion (PRKCA, EGFR, CDC42, VEGFA, etc.), Fc?R-mediated phagocytosis (PRKCA, CDC42, etc.), and so on. The 27 enriched pathways gradually deviated from baseline (namely, controls) along with the changes of obese-steatosis-NASH. In PPI networks, PRKCA interacted with EGFR and CDC42. Besides, hsa-miR-330-3p and hsa-miR-126 modulated focal adhesion through targeting VEGFA and CDC42. Conclusions. The identified DEGs (PRKCA, EGFR, CDC42, VEGFA), disturbed pathways (ribosome, ubiquitin mediated proteolysis, focal adhesion, Fc?R-mediated phagocytosis, etc.) and miRNAs (hsa-miR-330-3p, hsa-miR-126, etc.) might be closely related to NAFLD progression. These results might contribute to understanding NAFLD mechanism, conducting experimental researches, and designing clinical practices.
Background and rationale. Acoustic radiation force impulse (ARFI) is a non-invasive tool used in the evaluation of liver fibrosis in HCV positive immune-competent patients. This study aimed to assess the accuracy of ARFI in discriminating liver transplanted patients with different graft fibrosis severity and to verify whether ARFI, eventually combined with non-invasive biochemical tests, could spare liver biopsies. This prospective study included 51 HCV positive liver transplanted patients who consecutively underwent to annual liver biopsy concomitantly with ARFI and blood chemistry tests measurements needed to calculate several non-invasive liver fibrosis tests. Results. Overall ARFI showed an AUC of 0.885 in discriminating between patients without or with significant fibrosis (Ishak score 0-2vs. 3-6). Using a cut-off of 1.365 m/s, ARFI possesses a negative predictive value of 100% in identifying patients without significant fibrosis. AUC for Fibrotest was 0.848 in discriminating patients with Ishak fibrosis score 0-2 vs. 3-6. The combined assessment of ARFI and Fibro-test did not improve the results obtained by ARFI alone. Conclusion. ARFI measurement in HCV positive liver transplanted patients can be considered an easy and accurate non-invasive tool in identify patients with a benign course of HCV recurrence.
Background and aims. Concerns exist about outcomes of liver transplantation (LT) from low volume centres, especially for hepatitis C (HCV) patients. The aim of the study was to assess patient outcomes as well as their predictors post LT for HCV in a small volume Australian unit (< 25 LTs/year), comparing these with the average outcomes obtained from national and international transplant registries. Patients transplanted for HCV at the South Australian Liver Transplant Unit between 1992 and 2012 were studied. Outcomes assessed were patient and graft survival at 1,3, and 5 years. Factors independently associated with the outcomes were assessed using Cox regression model. Results. 1, 3, and 5-year patient survival for HCV patients was 95.2, 82.9, and 78.2%, graft survival were 93.7, 80.1, and 75.5% respectively. The total follow-up time observed was 299.9 years amongst 61 patients in which there were 16 deaths. The expected number of deaths was 40.4 and the standardized mortality ratio 0.40 (95% CI = 0.24, 0.65). These results compared favourably to those obtained from the SRTR registry. Variables independently associated with lower patient survival: donor age (HR = 1.06, 95% CI 1.02 - 1.11; P = 0.003), and post LT cytomegalovirus (CMV) disease requiring treatment (HR = 4.03, 95% CI 1.48 - 10.92;P = 0.06). Conclusion. In conclusion, high rates of patient and graft survival for HCV liver transplantation can be obtained in a small volume unit. Young donor age and lack of CMV disease post-transplant were associated with better outcomes. Institutional factors may be influential determinants of outcomes.
Introduction & Aim. The role of age as a predictor of mortality after transjugular intra hepatic portosystemic shunt (TIPS) is controversial. Age has been found to be an important predictor of post-TIPS mortality in some, but not all, studies and is not a component of the MELD score. The purpose of this study was to compare the 90-day survival of subjects with cirrhosis age ≥ 70 years with younger subjects undergoing TIPS. Material and methods. A database of adult with cirrhosis undergoing TIPS from 2003-2011 was analyzed. The primary endpoint was survival 90-days post-TIPS. Survival was analyzed by the Kaplan-Meier method and proportional hazard modeling. Results. 539 subjects met study criteria. 474 (88%) were between the ages of 24-69 and 65 (12%) were age 70-89 years. The groups were similar with respect to the indication for TIPS, mean MELD score and distribution of MELD score. Survival 90-days post-TIPS was 60% in the older cohort compared with 85% in the younger cohort (p < 0.001). Proportional hazards modeling controlled for comorbidities identified age ≥ 70 and MELD score as predictors of early post-TIPS survival. The hazard ratio associated with age increased monotonically, became significant at age ≥ 70 years (HR 3.22; 95% CI 1.81-5.74; p < 0.001) and exceeded the effect of MELD on survival. Conclusions. Age ≥ 70 was associated with reduced survival within 90 days following TIPS. The findings from this study indicate that age is a relevant consideration in assessing the early mortality risk of TIPS.
Background. Diagnosis of progressive familial intrahepatic cholestasis (PFIC) is a challenging matter that involves the summation of clinical, laboratory, radiological, and liver histological parameters; in addition to specific investigations to exclude other causes of neonatal cholestasis. The aim of this study was to evaluate liver tissue immunohistochemistry of bile salt export pump (BSEP) and multidrug resistance 3 (MDR3) proteins in differentiating PFIC from other causes of neonatal cholestasis, particularly, when genotyping is unavailable. Material and methods. The study included 25 patients diagnosed phenotypically as PFIC including 2 with PFIC1, 17 with PFIC2 and 6 with PFIC3. A second group of 25 cholestatic newborns with confirmed etiologies other than PFIC, termed as non-PFIC, included as controls. Liver biopsies from all patients were obtained and immunostained for BSEP and MDR3. Results. Negative immunoreaction of BSEP and MDR3 was found in the majority of PFIC group (76 and 64% respectively). Nonetheless, the negative immunoreaction was demonstrated in a considerable number of the non-PFIC group. BSEP immunoreaction was negative in the majority (82.4%) of PFIC2 but in none of the two patients with PFIC1. In addition, negative MDR3 immunoreaction was more frequently associated with PFIC3 compared to non-PFIC group. Conclusion. MDR3 and BSEP immunostaining would be a helpful tool in supporting the phenotypic diagnosis of PFIC subtypes and in differentiating PFIC from other causes of neonatal cholestasis.
Background and rationale for the study. There is currently no definition of post-transjugular intrahepatic portosystemic shunt (TIPS) liver failure (PTLF), which constitutes a barrier to standardization of TIPS results reporting and limits the ability to compare liver failure incidence across clinical studies. This descriptive study proposes and preliminarily tests the performance of a PTLF definition and grading system. Results. PTLF was defined by ≥ 3-fold bilirubin and/or ≥ 2-fold INR elevation associated with clinical outcomes of prolonged hospitalization/increase in care level (grade 1), TIPS reduction or liver transplantation (grade 2), or death (grade 3) within 30-days of TIPS. PTLF incidence was 20% (grades 1, 2, 3: 10%, 3%, 8%) among 270 TIPS cases, and the scheme identified patients at increased risk for morbidity and mortality with a statistically significant difference in clinical outcomes between PTLF and non-PTLF groups (P<0.0001). Conclusions. In conclusion, the PTLF definition and classification scheme put forth distributes patients into unique risk groups. PTLF grading may thus be useful for standardization of TIPS results reporting.
Background. Acute-on-chronic liver failure has high mortality. Currently, robust models for predicting the outcome of hepatitis B virus (HBV)-associated ACLF are lacking. Aim. To assess and compare the performance of six prevalent models for short- and longterm prognosis in patients with HBV-ACLF. Material and methods. The model for end-stage liver disease (MELD), MELD sodium (MELD-Na), MELD to sodium ratio (MESO), integrated MELD, Child-Turcotte-Pugh (CTP), and modified CTP (mCTP) were validated in a prospective cohort of 232 HBV-ACLF patients. The six models were evaluated by determining discrimination, calibration and overall performance at 3 months and 5 years. Results. According to the Hosmer-Lemeshow tests and calibration plots, all models could adequately describe the data except CTP at 3 months. Discrimination analysis showed that the iMELD score had the highest AUC of 0.76 with sensitivity of 62.6% and specificity of 80.2% for an optimal cut-off value of 52 at 3 months. It also had the highest AUC of 0.80 with sensitivity of 89.9% and specificity of 48.2% for an optimal cut-off value of 43 at 5 years. The overall performance of iMELD, assessed with Nagelkerkes R2 and the Brier score, was also the best among the six models. Conclusion. Integrated MELD may be the best model to predict short- and long-term prognosis in patients with HBV-ACLF.
Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. Material and methods. This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. Results. Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. Conclusions. Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.
Background/Purpose. In Japan, acute liver failure (ALF) has generally been described using the diagnostic term, fulminant hepatitis, because of the fact that most cases of ALF has been thought to occur in association with hepatitis mainly due to a hepatitis virus infection. New diagnostic criteria for ALF, including ALF other than fulminant hepatitis, were established in 2011. We therefore examined the prognostic factors of patients with liver failure from a systemic cause, including warfarin users. Material and methods. Sixty-six patients with ALF that were diagnosed according to the Japanese diagnostic criteria for ALF between 2009 and 2013 were divided into a survivor group and a non-survivor group. The data regarding demography, liver tests, coagulation tests, Sequential Organ Failure Assessment (SOFA) scores, and the use of oral warfarin or aspirin were compared between the two groups. Results. The SOFA score was significantly higher in the non-survivor group (p = 0.025). The proportion of oral warfarin users was significantly higher in the survivor group (p = 0.013) (58.1% vs. 26.1%). A multivariate logistic regression analysis showed the SOFA score (odds ratio: 0.851, 95% confidence interval (CI): 0.728-0.995, p = 0.043) and warfarin use (odds ratio: 3.261, 95% CI: 1.028-10.347, p = 0.045) to be significant factors that were negatively and positively associated with the prognosis, respectively. Conclusion. In this study, among the patients with ALF other than fulminant hepatitis, those with a high SOFA score on admission exhibited a poor prognosis. In addition, oral warfarin use prior to disease onset was found to be a factor which indicated a good prognosis.
Background: Uncontrolled hapatic inflammatory response is regarded as the primary pathological mechanism of acute liver failure and impairs the regeneration of hepatocytes and stem cell grafts. Interleukin-1 plays a key role for activating immune and inflammatory response. Recently, siRNA has made quite a few progresses in treating inflammatory response. Aim. To assess the effect of IL-1? siRNA adenovirus on MSC and the therapeutic effect of MSC combined with IL-1? siRNA adenovirus in ALF. Material and methods. We implanted MSC or/and IL-1? siRNA adenovirus via the tail vein, using CCl4-induced ALF in a mice model. Mice were sacrificed at different time points. Blood samples and liver tissues were collected. Hepatic injury, liver regeneration, cytokines (CXCL1, IL-1?, IL-10, IL-6, VEGF and HGF), animal survival and vital MSC were assessed after cell transplantation. Results. MSC combined with IL-1? siRNA reduced the inflammatory levels and prevented liver failure. These animals administrated with MSC and IL-1? siRNA also exhibited improved liver regeneration and increased survival rates. Immunohistochemistry and fluorescence microscopy revealed the number of vital MSC in ALF + MSC + IL-1? siRNA group were significantly more than that in ALF + MSC group. Conclusion. IL-1? siRNA adenovirus could enhance MSC ability of tissue regeneration through increasing its survival rate. Accordingly, combination of IL-1? siRNA adenovirus and MSC had a synergistic effect on acute liver failure.
Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor indicated for treatment of patients with chronic hepatitis B virus (CHB) and human immunodeficiency virus (HIV) infections. Despite the good safety profile of the drug, Fanconi syndrome is a possible adverse reaction of TDF treatment, especially in HIV-infected patients. Only a few cases have been reported in patients with CHB-monoinfections. This report presents a case of a 58-year-old man with mild HBeAg-negative CHB who was exposed to TDF and developed drug-induced Fanconi syndrome. Renal dysfunction reverted after TDF discontinuation and a switch to entecavir, and viral replication remained suppressed. A literature review yielded six additional cases of TDF-induced Fanconi syndrome, all with risk factors for renal dysfunction despite the patients having normal glomerular filtration rates. We discuss the overall risk for Fanconi syndrome in CHB-monoinfected patients exposed to TDF and the importance of careful monitoring of glomerular and tubular functions even when pre-existing kidney disease is not present.
Multiple genetic and environmental factors interact to determine an individuals predisposition to non-alcoholic fatty liver disease and its phenotypic characteristics. Association studies have found a number of alleles associated with the development of non-alcoholic steatohepatitis. Our aim was to investigate whether multiple risk-associated alleles may be present in affected monozygotic twins, indicating underlying genetic predisposition to non-alcoholic steatohepatitis. We determined the genotype of 14 candidate gene polymorphisms (at 11 unlinked loci) in a set of monozygotic twins who presented with cirrhosis within 18 months of each other. Genotyping revealed multiple single nucleotide polymorphisms at 9 independent loci in genes PNPLA3, APOC3, GCKR, TRIB1, LYPLAL1, PPP1R3B, COL13A1, and EFCAB4B, previously implicated in contributing to non-alcoholic steatohepatitis pathogenesis. In conclusion, this case series illustrates the potential cumulative effect of multiple polymorphisms in the development and potential progression of a complex trait such as NASH cirrhosis.
We report an example of a cystic hepatic angiosarcoma that to our knowledge has not been previously described. The patient was a 70 year old woman who was admitted to the emergency room because of hypovolemic shock. A computed tomography showed four heterogeneous hepatic cystic masses varying from 2.5 to 11.2 cm; one of these with rupture and formation of a subcapsular hematoma. The cyst wall was lined by several layers of neoplastic epithelioid and spindle shaped endothelial cells that in some areas extended to the underlying stroma. They expressed CD31 and CD34, and were negative for cytokeratin. The patient is alive with residual hepatic cystic angiosarcoma. However, follow up is too short to be significant.